1. Field of the Invention
The present invention relates to a novel connective tissue growth factor. More specifically, isolated nucleic acid molecules are provided encoding a human connective tissue growth factor-3. Connective tissue growth factor-3 polypeptides are also provided, as are vectors, host cells, and recombinant methods for producing the same. Also provided are diagnostic and therapeutic methods for detecting and treating connective tissue related disorders.
2. Background Art
Growth factors are a class of secreted cysteine-rich polypeptides that stimulate target cells to proliferate, differentiate, and organize in developing tissues. The action of growth factors is dependent on their binding to specific receptors, which stimulate a signaling event within the cell. Examples of some well-studied growth factors include platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I), transforming growth factor beta (TGF-β), transforming growth factor alpha (TGF-α), epidermal growth factor (EGF), and fibroblast growth factor (FGF). This group of growth factors is important for normal growth, differentiation, morphogenesis of the cartilaginous skeleton of an embryo, and cell growth. Among some of the functions that have been reported for these growth factors are wound healing, tissue repair/regeneration, implant fixation, and stimulating bone mass increase.
PDGF is a cationic, heat-stable protein found in the alpha-granules of circulating platelets and is known to be a mitogen and chemotactic agent for connective tissue cells such as fibroblasts and smooth muscle cells. Because of the activities of this molecule, PDGF is believed to be a major factor involved in the normal healing of wounds and pathologically contributes to such diseases as atherosclerosis and fibrotic diseases. PDGF is a dimeric molecule consisting of an A chain and a B chain. The chains form heterodimers or homodimers and all combinations isolated to date are biologically active.
Studies on the role of various growth factors in tissue regeneration and repair have led to the discovery of PDGF-like proteins. These proteins share both immunological and biological activities with PDGF and can be blocked with antibodies specific to PDGF.
U.S. Pat. No. 5,408,040 to Grotendorst et al. (1995) discloses a PDGF-like protein called Connective Tissue Growth Factor (CTGF) that reportedly plays a significant role in the normal development, growth, and repair of human tissue. The discovery of the CTGF protein and the cloning of the cDNA encoding the protein was reportedly significant in that it was a previously unknown growth factor having mitogenic and chemotactic activities for connective tissue cells. Although the biological activity of CTGF was similar to that of PDGF, CTGF is the product of a gene unrelated to the A or B chain genes of PDGF.
Since CTGF is produced by endothelial and fibroblastic cells, both of which are present at the site of a wound, it is probable that CTGF functions as a growth factor in wound healing. Accordingly, it is believed that the CTGF polypeptide could be used as a therapeutic in cases in which there is impaired healing of skin wounds or where there is a need to augment the normal healing process.
Pathologically, CTGF may also be involved in diseases in which there is an overgrowth of connective tissue cells or an enhanced production of extracellular matrix components. Such diseases include cancer, fibrosis, and atherosclerosis. For example, it has been shown that CTGF gene expression is elevated in the skin of patients with systemic sclerosis (SSc). Igarashi et al., J. Invest. Dermatol. 105:280-284 (1995). CTGF gene expression has also recently been demonstrated in several fibrotic skin diseases, such as localized scleroderma, keloid scars, nodular fasciatus, and eosinophilic fasciatus, suggesting a pathogenic role for this molecule in skin fibrosis. Igarashi et al., J. Invest. Dermatol. 106:729-733 (1996). Oemar et al., Circulation 92(8), Supp't 1, Abstract 0811 (October 1995) have reported that human CTGF is expressed at 5-10 fold higher levels in the aorta, a tissue prone to develop atherosclerosis, as compared to expression levels in internal mammary arteries, which are resistant to atherosclerosis. Their results suggest that hCTGF may play an essential role in the development and progression of atherosclerosis. Therapeutically, it has been reported in U.S. Pat. No. 5,408,040 to Grotendorst et al. (1995) that CTGF antibodies or fragments of the antibody could be used to neutralize the biological activity of CTGF in diseases where CTGF is inducing the overgrowth of tissue. Additionally, antibodies to CTGF polypeptide or fragments could be valuable as diagnostic tools to aid in the detection of diseases in which CTGF is a pathological factor. Id.
Due to the important role of CTGF in the development and repair of human tissue, as well as its role in the development and progression of various connective-tissue related disorders, there is a clear need in the art for the identification of new connective tissue growth factors that can be utilized in the development of diagnostics and therapeutics for various connective tissue related disorders.